ABSTRACT The major cause of death for nearly all men with prostate cancer is metastasis of therapy-resistant disease. Current standard-of-care therapies to treat metastatic castration-resistant prostate cancer (mCRPC) include novel hormonal agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide. These hormonal therapies have significantly prolonged survival of men with mCRPC; however, acquired resistance to these drugs is inevitable within 1-2 years. Therefore, there is a major unmet clinical need to identify mechanisms of resistance and innovative therapies to treat hormone therapy-resistant disease. In our preliminary studies, we have determined that enzalutamide promotes evolutionary selection for cells with a pro-survival, immuno-evasive, and metastatic phenotype mediated by a p38?/Snail/PD-L1 gene regulatory network. Our central hypothesis is that the p38?/Snail/PD-L1 axis promotes both cell-intrinsic hormone therapy resistance and cell-extrinsic immune evasion. The main objective of this R01 proposal is to interrogate the importance of p38? and cellular plasticity signaling with hormone resistance and immune evasion in preclinical studies and in patients with metastatic prostate cancer. In aim 1, we will test the potential of p38? as a cell intrinsic mechanism of AR therapy resistance and metastasis, and overcome this induced resistance with small molecule p38? inhibition in the mCRPC setting. To accomplish this goal, we will conduct both preclinical mechanistic studies in vivo and clinical correlative analyses in circulating tumor cells and metastatic biopsies from men with mCRPC. In aim 2, we will test the hypothesis that the p38?/Snail/PD-L1 axis mediates cell extrinsic immune evasion in AR therapy resistant tumors. Using immunocompetent transgenic mouse models and patient-derived xenografts with humanized immune systems, we will mechanistically assess the relationship between p38? and PD-L1 upregulation, dissect the downstream effects of p38? activation, and explore the therapeutic benefit of targeting the p38?/PD-L1 axis in AR therapy resistant mCRPC. We will couple these experiments to clinical correlative analysis using banked circulating tumor cells and metastatic tissues previously collected from men with mCRPC before and after progression on abiraterone acetate or enzalutamide. Our data provide strong evidence that AR therapy resistance converges on a p38?/Snail/PD-L1 stress- plasticity axis that can be therapeutically targeted to improve clinical outcomes in prostate cancer. The overall goal of this proposal is to provide the preclinical and clinical correlative studies to justify clinical trials to provide near-term benefit for men with metastatic, hormone therapy-resistant prostate cancer.